Human adipose-derived mesenchymal stem cells (hAMSCs) are capable of immunomodulation and regeneration after neural injury. For these reasons, hAMSCs have been investigated as a promising stem cell candidate for stroke treatment. However, noninvasive experiments studying the effects of grafted stem cells in the host brain have not yet been reported. Cerebrospinal fluid (CSF), which can be collected without sacrificing the subject, is involved in physiological control of the brain and reflects the pathophysiology of various neurological disorders of the central nervous system (CNS). Following stem cell transplantation in a stroke model, quantitative analysis of CSF proteome changes can potentially reveal the therapeutic effect of stem cells on the host CNS. We examined hAMSC-secreted proteins obtained from serum-free culture medium by liquid chromatography-tandem mass spectrometry (LC-MS/MS), which identified several extracellular matrix proteins, supporting the well-known active paracrine function of hAMSCs. Subsequently, we performed label-free quantitative proteomic analysis on CSF samples from rat stroke models intravenously injected with hAMSC (experimental) or phosphate buffered saline (control). In total, 524 proteins were identified; among them, 125 and 91 proteins were increased and decreased with hAMSC treatment, respectively. Furthermore, gene set enrichment analysis revealed three proteins, 14-3-3 theta, MAG, and neurocan, that showed significant increases in the hAMSC-treated model; these proteins are core members of neurotrophin signaling, nerve growth factor (NGF) signaling, and glycosaminoglycan metabolism, respectively. Subsequent histological and neurologic function experiments validated proliferative neurogenesis in the hAMSC-treated stroke model. We conclude that (i) intravenous injection of hAMSCs can induce neurologic recovery in a rat stroke model and (ii) CSF may reflect the therapeutic effect of hAMSCs. Additionally, proteins as 14-3-3 theta, MAG, and neurocan could be considered as potential CSF biomarkers of neuroregeneration. These CSF proteome profiling results would be utilized as valuable resource in further stroke studies.
Bibliographical noteFunding Information:
The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported in part by grants from Korea University (K1913911, K2011341); the Basic Science Research Program through the National Research Foundation (NRF) funded by the Korean Ministry of Education, Science and Technology (NRF-2013R1A1A2057994); and the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (HI12C03370400) to Dong-Hyuk Park. This study was also supported in part by a grant from the Collaborative Genome Program for Fostering New Post-Genome Industry (NRF-2017M3C9A5031597) of the National Research Foundation funded by the Korean Ministry of Science and ICT to Sang Won Lee. We would also like to acknowledge the financial support from the Korea Healthcare Technology R&D Project (HI16C1002) and the Basic Science Research Program through the National Research Foundation (NRF-2017R1D1A1B03035760, NRF-2019R1C1C1010602, NRF-2017M3C7A1027472) funded by the Korean Ministry of Education, Science and Technology.
© The Author(s) 2021.
ASJC Scopus subject areas
- General Medicine